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J. Biol. Chem., Vol. 282, Issue 4, 2520-2528, January 26, 2007

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Preservation of Antimicrobial Properties of Complement Peptide C3a, from Invertebrates to Humans^*

Mukesh Pasupuleti, Björn Walse, Emma Andersson Nordahl, Matthias Mörgelin^¶, Martin Malmsten^||, and Artur Schmidtchen¹

From the Section of Dermatology and Venereology, ^¶Section of Clinical and Experimental Infectious Medicine, Department of Clinical Sciences, Biomedical Center, Lund University, Tornavägen 10, SE-221 84 Lund, SARomics AB, P.O. Box 724, SE-220 07 Lund, ^||Department of Pharmacy, Uppsala University, SE-751 23 Uppsala, Sweden

The human anaphylatoxin peptide C3a, generated during complement activation, exerts antimicrobial effects. Phylogenetic analysis, sequence analyses, and structural modeling studies paired with antimicrobial assays of peptides from known C3a sequences showed that, in particular in vertebrate C3a, crucial structural determinants governing antimicrobial activity have been conserved during the evolution of C3a. Thus, regions of the ancient C3a from Carcinoscorpius rotundicauda as well as corresponding parts of human C3a exhibited helical structures upon binding to bacterial lipopolysaccharide permeabilized liposomes and were antimicrobial against Gram-negative and Gram-positive bacteria. Human C3a and C4a (but not C5a) were antimicrobial, in concert with the separate evolutionary development of the chemotactic C5a. Thus, the results demonstrate that, notwithstanding a significant sequence variation, functional and structural constraints imposed on C3a during evolution have preserved critical properties governing antimicrobial activity.

Received for publication, August 16, 2006 , and in revised form, November 8, 2006.

^* This work was supported by grants from the Swedish Research Council (Projects 13471 and 621-2003-4022), the Royal Physiographic Society in Lund, the Welander-Finsen, Söderberg, Schyberg, Groschinsky, Crafoord, Åhlen, Alfred Österlund, Lundgrens, Lions, and Kock Foundations, and the Swedish Government Funds for Clinical Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1 and Tables 1 and 2.

¹ To whom correspondence should be addressed: Section of Dermatology and Venereology, Dept. of Clinical Sciences, Lund University, Biomedical Ctr., Tornavägen 10, SE-22184 Lund, Sweden. Tel.: 46-46-222-4522; Fax: 46-46-157-756; E-mail: artur.schmidtchen{at}med.lu.se.

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